Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models.

Abstract

BACKGROUND:

The clinical responses to chemotherapy in lung cancer patients are unsatisfactory. Thus, the development of more effective anticancer drugs for lung cancer is urgently needed.

METHODS:

A 2-step novel synthetic compound, referred to as 1,1,3-tri(3-indolyl)cyclohexane (3-indole), was generated in high purity and yield. 3-Indole was tested for its biologic activity in A549, H1299, H1435, CL1-1, and H1437 lung cancer cells. Animal studies were also performed.

RESULTS:

The data indicate that 3-indole induced apoptosis in various lung cancer cells. Increased cytochrome-c release from mitochondria to cytosol, decreased expression of antiapoptotic Bcl-2, and increased expression of proapoptotic Bax were observed. In addition, 3-indole stimulated caspases-3, -9, and to a lesser extent caspase-8 activities in cancer cells, suggesting that the intrinsic mitochondria pathway was the potential mechanism involved in 3-indole-induced apoptosis. 3-Indole-induced a concentration-dependent mitochondrial membrane potential dissipation and an increase in reactive oxygen species (ROS) production. Activation of c-Jun N-terminal kinase (JNK) and triggering of DNA damage were also apparent. Note that 3-indole-induced JNK activation and DNA damage can be partially suppressed by an ROS inhibitor. Apoptosis induced by 3-indole could be abrogated by ROS or JNK inhibitors, suggesting the importance of ROS and JNK stress-related pathways in 3-indole-induced apoptosis. Moreover, 3-indole showed in vivo antitumor activities against human xenografts in murine models.

CONCLUSIONS:

On the basis of its potent anticancer activity in cell and animal models, the data suggest that this 2-step synthetic 3-indole compound of high purity and yield is a potential candidate to be tested as a lead pharmaceutical compound for cancer treatment.

• Authors: Ching-Hsiao Lee, Ching-Fa Yao, Sin-Ming Huang, Shengkai Ko, Yi-Hung Tan, Guey-Jen Lee-Chen, Yi-Ching Wang
• Journal: Cancer (Cancer) Vol. 113 Issue 4 Pg. 815-25 (Aug 15 2008) ISSN: 0008-543X [Print] United States
• PMID: 18618576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2008 American Cancer Society

Chemical References

• 1,1,3-tris(3-indolyl)cyclohexane
• Cyclohexanes
• Indoles
• Reactive Oxygen Species
• Cyclohexane
• indole

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclohexanes (therapeutic use)
• DNA Damage
• Female
• Humans
• Indoles (therapeutic use)
• Lung Neoplasms (drug therapy)
• Mice
• Mice, Nude
• Oligonucleotide Array Sequence Analysis
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays